• Jerry R Mendell, Louise R Rodino-Klapac, Zarife Sahenk, Kandice Roush, Loren Bird, Linda P Lowes, Lindsay Alfano, Ann Maria Gomez, Sarah Lewis, Janaiah Kota, Vinod Malik, Kim Shontz, Christopher M Walker, Kevin M Flanigan, Marco Corridore, John R Kean, Hugh D Allen, Chris Shilling, Kathleen R Melia, Peter Sazani, Jay B Saoud, Edward M Kaye, and Eteplirsen Study Group.
• Departments of Pediatrics, Ohio State University, Columbus, OH; Neurology the Ohio State University, Ohio State University, Columbus, OH; Gene Therapy Center, Nationwide Children's Hospital Ohio State University, Columbus, OH; Paul D. Wellstone Center, Nationwide Children's Hospital Ohio State University, Columbus, OH.
• Ann. Neurol. 2013 Nov 1;74(5):637-47.

ObjectiveIn prior open-label studies, eteplirsen, a phosphorodiamidate morpholino oligomer, enabled dystrophin production in Duchenne muscular dystrophy (DMD) with genetic mutations amenable to skipping exon 51. The present study used a double-blind placebo-controlled protocol to test eteplirsen's ability to induce dystrophin production and improve distance walked on the 6-minute walk test (6MWT).MethodsDMD boys aged 7 to 13 years, with confirmed deletions correctable by skipping exon 51 and ability to walk 200 to 400 m on 6 MWT, were randomized to weekly intravenous infusions of 30 or 50 mg/kg/wk eteplirsen or placebo for 24 weeks (n = 4/group). Placebo patients switched to 30 or 50 mg/kg eteplirsen (n=2/group) at week 25; treatment was open label thereafter. All patients had muscle biopsies at baseline and week 48. Efficacy included dystrophin-positive fibers and distance walked on the 6MWT.ResultsAt week 24, the 30 mg/kg eteplirsen patients were biopsied, and percentage of dystrophin-positive fibers was increased to 23% of normal; no increases were detected in placebo-treated patients (p≤0.002). Even greater increases occurred at week 48 (52% and 43% in the 30 and 50 mg/kg cohorts, respectively), suggesting that dystrophin increases with longer treatment. Restoration of functional dystrophin was confirmed by detection of sarcoglycans and neuronal nitric oxide synthase at the sarcolemma. Ambulation-evaluable eteplirsen-treated patients experienced a 67.3 m benefit compared to placebo/delayed patients (p≤0.001).InterpretationEteplirsen restored dystrophin in the 30 and 50 mg/kg/wk cohorts, and in subsequently treated, placebo-controlled subjects. Duration, more than dose, accounted for dystrophin production, also resulting in ambulation stability. No severe adverse events were encountered.© 2013 American Neurological Association.

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